Excitatory and inhibitory responses of dopamine neurons in the ventral tegmental area to nicotine.

In the present electrophysiological study the mechanisms by which nicotine activates dopamine neurons in the ventral tegmental area in anesthetized Sprague-Dawley rats were analyzed. Intravenous administration of nicotine caused a dose-dependent increase in firing rate and percentage of spikes fired in bursts of ventral tegmental area dopamine neurons. However, this activation was preceded by an instantaneous but short-lasting inhibition of the firing rate. The excitation of dopamine neurons by nicotine (1.5-400 microg/kg i.v.) was antagonized and even reversed into an inhibitory response by elevated levels (four-fold) of the endogenous glutamate receptor antagonist kynurenic acid, as induced by a potent inhibitor of kynurenine 3-hydroxylase (PNU 156561A, 40 mg/kg, i.v., 5-9 h). The antagonistic action induced by PNU 156561A pretreatment was prevented by administration of D-cycloserine (128 mg/kg, i.v., 5 min). Administration of the GABA(B)-receptor antagonist CGP 35348 (200 mg/kg, i.v., 3 min) facilitated the nicotine-induced increase in burst firing activity of dopamine neurons and antagonized the short-lasting decrease in firing rate by nicotine. The results of the present study show that nicotine produces both inhibition and excitation of ventral tegmental area dopamine neurons, actions that appear to be related to the release of GABA and glutamate, respectively. Whereas the excitatory action of nicotine may be associated with motivational processes underlying learning and cognitive behavior, the inhibitory action of the drug may play a more prominent role in the situation of a profound dysregulation of the mesocorticolimbic dopamine system and may help to explain the high prevalence of tobacco-smoking in schizophrenics.